Group A Streptococcus (GAS) is a major cause of human mortality and morbidity worldwide. Therefore, understanding the molecular mechanisms by which GAS colonizes and invades human hosts is important for the development of new anti-streptococcal therapies. It is clear that cell surface GAS products participate in disease. Two recently identified streptococcal genes, scl1 and scl2, encode cell surface proteins that contain Gly-X-X collagen-like repeats. This last characteristic of Scl is particularly intriguing due to the fact that antibodies against streptococcal cell-wall antigens cross-react with human-tissue antigens, resulting in post-infection autoimmunity. However, nothing is known about Scl protein expression in vivo and antigenicity for the host. The long-term objective of the proposed work is to determine the importance of Scl in GAS adherence to and invasion of human cells and to evaluate the role of anti-SCL response in human autoimmune diseases. This project will test the hypotheses that (a) Scl virulence factors contribute to Gas pathogenesis, (b) expression of scl genes is coordinately regulated by various control mechanisms and many GAS strains simultaneously produce both Scl1 and Scl2 proteins, and (d) Scl proteins are expressed in vivo and anti-Scl-specific antibodies are produced by the infected host. The specific aims are as follows: First, determine whether Scl proteins participate in the pathogenesis of different disease types caused by GAS by constructing genetically defined isogenic scl1 and scl2 mutants of GAS strains and testing them in mouse infection models; second, determine whether Scl proteins contribute to GAS adherence to human cultered cells and extracellular matrix components; third, determine transcriptional and translational mechanisms controlling scl gene expression and whether GAS strains simultaneously produce both Scl proteins; and fourth, analyze expression of Scl proteins within infected tissue and production of anti-Scl-specific antibodies in human sera and in experimental models. The proposed studies will provide new directions for the development of anti-streptococcal therapies and, in light of the existence of the collagen- like antigen Scl on the surface of GAS, may have important implications for future studies of human autoimmune diseases.